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Clinical Pharmacy
Chapter Three
Ischemic heart disease (IHD)
Rowa’ Al-Ramahi
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DEFINITION
• Ischemic heart disease (IHD) is defined as a lack of
oxygen and decreased or no blood flow to the
myocardium resulting from coronary artery narrowing or
obstruction. IHD may present as an acute coronary
syndrome (ACS, which includes unstable angina and
non–ST-segment elevation or ST-segment elevation
myocardial infarction [MI]), chronic stable exertional
angina, ischemia without symptoms, or ischemia due to
coronary artery vasospasm (variant or Prinzmetal
angina).
• Relatively severe stenosis (greater than 70%) may
provoke ischemia and symptoms at rest, whereas less
severe stenosis may allow a reserve of coronary blood
flow for exertion.
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CLINICAL PRESENTATION
• Many episodes of ischemia do not cause symptoms (silent
ischemia). Patients often have a reproducible pattern of pain
that appear after a specific amount of exertion. Increased
symptom and symptoms at rest suggest an unstable pattern
that requires immediate medical evaluation.
• Symptoms may include a sensation of pressure or burning
over the sternum or near it, which often radiates to the left
jaw, shoulder, and arm. Chest tightness and shortness of
breath may also occur. The sensation usually lasts from 30
seconds to 30 minutes.
• Precipitating factors include exercise, cold environment,
walking after a meal, emotional upset, fright, anger, and
coitus. Relief occurs with rest and within 45 seconds to 5
minutes of taking nitroglycerin.
• Patients with variant or Prinzmetal angina secondary to
coronary spasm are more likely to experience pain at rest
and in the early morning hours. Pain is not usually brought
on by exertion or emotional stress nor is it relieved by rest;
ECG pattern is that of current injury with ST-segment
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elevation rather than depression.
DIAGNOSIS
• Important aspects of the clinical history include the
nature or quality of the chest pain, precipitating factors,
duration, pain radiation, and the response to nitroglycerin
or rest.
• The patient should be asked about existing personal risk
factors for CHD including smoking, hypertension, and
diabetes mellitus.
• A detailed family history should be obtained .
• Cardiac enzymes should all be normal in stable angina.
Troponin T or I, myoglobin, and creatinine kinase MB
may be elevated in nunstable angina.
• ECG
• Exercise tolerance (stress) testing (ETT)
• Radionuclide angiocardiography
• Ultrarapid computed tomography
• Echocardiography
• Cardiac catheterization and coronary angiography
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• Chest radiograph
DESIRED OUTCOME
• The short-term goals of therapy for IHD are to reduce or
prevent anginal symptoms that limit exercise capability
and impair quality of life.
• Long term goals are to prevent CHD events such as MI,
arrhythmias, and heart failure and to extend the patient’s
life.
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TREATMENT
• RISK-FACTOR MODIFICATION
• Primary prevention through the modification of risk
factors should significantly reduce the prevalence of IHD.
Secondary intervention is effective in reducing
subsequent morbidity and mortality.
• Unalterable risk factors include gender, age, family
history or genetic composition, environmental influences,
and, to some extent, diabetes mellitus. Alterable risk
factors include smoking, hypertension, hyperlipidemia,
obesity, sedentary lifestyle, hyperuricemia, psychosocial
factors such as stress and type A behavior patterns, and
the use of drugs that may be detrimental (e.g.,
progestins, corticosteroids, and cyclosporine). Although
thiazide diuretics and β-blockers (nonselective without
intrinsic sympathomimetic activity) may elevate both
cholesterol and triglycerides by 10% to 20%, and these
effects may be detrimental, no objective evidence exists
from prospective well-controlled studies to support
avoiding these drugs.
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PHARMACOLOGIC THERAPY
β-Adrenergic Blocking Agents
• β-Blockers improve symptoms in about 80% of patients
with chronic exertional stable angina. β-Blockade may
allow angina patients previously limited by symptoms to
perform more exercise and ultimately improve overall
cardiovascular performance through a training effect.
• Ideal candidates for β-blockers include patients in whom
physical activity is a prominent cause of attacks; those
with
coexisting
hypertension,
supraventricular
arrhythmias, or postmyocardial infarction angina; and
those with anxiety associated with anginal episodes. βBlockers may be used safely in angina and heart failure.
• β-Blockade is effective in chronic exertional angina as
monotherapy and in combination with nitrates and/or
calcium channel antagonists. β-Blockers are the first-line
drugs in chronic angina requiring daily maintenance
therapy.
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• If β-blockers are ineffective or not tolerated, then
monotherapy with a CCB or combination therapy may be
instituted. Reflex tachycardia from nitrates can be
blunted with β-blocker therapy, making this a useful
combination. Patients with severe angina, rest angina, or
variant angina may be better treated with CCB or longacting nitrates.
• Treatment objectives include lowering the resting HR to
50 to 60 beats/min and limiting maximal exercise HR to
about 100 beats/min or less. HR with modest exercise
should be no more than about 20 beats/min above
resting HR (or a 10% increment over resting HR).
• There is little evidence to suggest superiority of any
particular β-blocker. Intrinsic sympathomimetic activity
appears to be detrimental in patients with rest or severe
angina because the reduction in HR would be minimized,
therefore limiting a reduction in MVO2.
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• Cardioselective β-blockers may be used in some
patients to minimize adverse effects such as
bronchospasm, intermittent claudication, and sexual
dysfunction. Combined nonselective β- and α-blockade
with labetalol may be useful in some patients with
marginal left ventricular (LV) reserve.
• Adverse effects of β-blockade include hypotension, heart
failure, bradycardia, heart block, bronchospasm, altered
glucose metabolism, fatigue, malaise, and depression.
Abrupt withdrawal in patients with angina has been
associated with increased severity and number of pain
episodes and MI. Tapering of therapy over about 2 days
should minimize the risk of withdrawal reactions if
therapy is to be discontinued.
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Nitrates
• Nitrate therapy may be used to terminate an acute
anginal attack, to prevent effort- or stress-induced
attacks, or for long-term prophylaxis, usually in
combination with β-blockers or calcium channel
antagonists. Sublingual, buccal, or spray nitroglycerin
products are preferred for alleviation of anginal attacks
because of rapid absorption. Symptoms may be
prevented by prophylactic oral or transdermal products
(usually in combination with β-blockers or calcium
channel antagonists), but development of tolerance may
be problematic.
• Sublingual nitroglycerin relieves pain in about 75% of
patients within 3 minutes, with another 15% becoming
pain-free in 5 to 15 minutes. Pain persisting beyond 20
to 30 minutes after use of two to three nitroglycerin
tablets suggests ACS, and the patient should be
instructed to seek emergency aid.
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• Chewable, oral, and transdermal products are acceptable for
long-term prophylaxis of angina.
• Adverse effects include postural hypotension with
associated CNS symptoms, reflex tachycardia, headaches
and flushing, and occasional nausea. Excessive hypotension
may result in MI or stroke. Noncardiovascular adverse
effects include rash (especially with transdermal
nitroglycerin) and methemoglobinemia with high doses given
for extended periods. Because both the onset and offset of
tolerance to nitrates occur quickly, one strategy to
circumvent it is to provide a daily nitrate-free interval of 8 to
12 hours. For example, ISDN should not be used more often
than three times a day to avoid tolerance.
• Nitrates may be combined with other drugs with
complementary mechanisms of action for chronic
prophylactic therapy. Combination therapy is generally used
in patients with more frequent symptoms or symptoms that
do not respond to Β -blockers alone (nitrates plus Β blockers or CCB), in patients intolerant of β-blockers or CCB,
and in patients having an element of vasospasm leading to
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decreased supply (nitrates plus CCB).
Calcium Channel Antagonists
• Verapamil and diltiazem cause less peripheral
vasodilation than dihydropyridines such as nifedipine
but greater decreases in AV node conduction. They must
be used with caution in patients with preexisting
conduction abnormalities or in patients taking other
drugs with negative chronotropic properties.
• In contrast to the β-blockers, calcium channel
antagonists have the potential to improve coronary blood
flow through areas of fixed coronary obstruction by
inhibiting coronary artery vasomotion and vasospasm.
• Good candidates for calcium channel antagonists
include patients with contraindications or intolerance to
β-blockers, coexisting conduction system disease
(excluding the use of verapamil and possibly diltiazem),
Prinzmetal angina, peripheral vascular disease, severe
ventricular dysfunction, and concurrent hypertension.
Amlodipine is probably the agent of choice in severe
ventricular dysfunction, and the other dihydropyridines
should be used with caution if the EF is less than 40%. 12
•
•
•
•
Ranolazine
The mechanism of action of ranolazine has not been
determined, but it may be related to reduction in calcium
overload in ischemic myocytes through inhibition of the
late sodium current. Its antianginal effects do not depend
on reductions in HR or blood pressure.
Ranolazine is indicated for the treatment of chronic
angina. Based on controlled trials, the improvement in
exercise time is a modest increase of 15 to about 45
seconds compared with placebo.
Because it prolongs the QT interval, ranolazine should
be reserved for patients who have not achieved an
adequate response to other antianginal drugs. It should
be used in combination with amlodipine, β-blockers, or
nitrates.
The most common adverse effects are dizziness,
headache, constipation, and nausea. Baseline and follow
up ECGs should be obtained to evaluate effects on the
QT interval.
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TREATMENT OF STABLE EXERTIONAL ANGINA PECTORIS
• After assessing and manipulating alterable risk factors, a
regular exercise program should be undertaken with
caution in a graduated fashion and with adequate
supervision to improve cardiovascular and muscular
fitness.
• Nitrate therapy should be the first step in managing acute
attacks of chronic stable angina if the episodes are
infrequent (e.g., a few times per month). If angina occurs
no more often than once every few days, then sublingual
nitroglycerin tablets or spray or buccal products may be
sufficient.
• For prophylaxis when undertaking activities that
predictably precipitate attacks, nitroglycerin 0.3 to 0.4 mg
sublingually may be used about 5 minutes prior to the time
of the activity. Nitroglycerin spray may be useful when
inadequate saliva is produced to rapidly dissolve
sublingual nitroglycerin or if a patient has difficulty
opening the tablet container. The response usually lasts
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about 30 minutes.
• When angina occurs more frequently than once a day,
chronic prophylactic therapy should be instituted. βBlockers may be preferable because of less frequent
dosing and other desirable properties (e.g., potential
cardioprotective effects, antiarrhythmic effects, lack of
tolerance, antihypertensive efficacy). Patients most likely
to respond well to β-blockade are those with a high
resting HR and those with a relatively fixed anginal
threshold (i.e., their symptoms appear at the same level
of exercise or workload on a consistent basis).
• Calcium channel antagonists may be used instead of
β-blockers for chronic prophylactic therapy. They are as
effective as β-blockers and are most useful in patients
who have a variable threshold for exertional angina.
Calcium antagonists may provide better skeletal muscle
oxygenation, resulting in decreased fatigue and better
exercise tolerance. They can be used safely in many
patients with contraindications to β-blocker therapy. The
available drugs have similar efficacy in the management
of chronic stable angina.
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• Patients with conduction abnormalities and moderate to
severe LV dysfunction (EF <35%) should not be treated
with verapamil, whereas amlodipine may be used
safely in many of these patients. Diltiazem has
significant effects on the AV node and can produce heart
block in patients with preexisting conduction disease or
when other drugs with effects on conduction (e.g.,
digoxin, β-blockers) are used concurrently. Nifedipine
may cause excessive HR elevation, especially if the
patient is not receiving a β-blocker, and this may offset
its beneficial effect on MVO2. The combination of CCB
and β-blockers is rational because the hemodynamic
effect of CCB is complementary to β-blockade. However,
combination therapy may not always be more effective
than single-agent therapy.
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• Chronic prophylactic therapy with long-acting forms of
nitroglycerin (oral or transdermal), ISDN, ISMN, and
pentaerythritol trinitrate may also be effective when
angina occurs more than once a day, but development of
tolerance is a limitation. Monotherapy with nitrates
should not be first-line therapy unless β-blockers and
CCB are contraindicated or not tolerated. A nitrate-free
interval of 8 hours per day or longer should be provided
to maintain efficacy. Dose titration should be based on
changes in the DP. The choice among nitrate products
should be based on experience, cost, and patient
acceptance.
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TREATMENT OF CORONARY ARTERY SPASM
AND VARIANT ANGINA PECTORIS
• All patients should be treated for acute attacks and
maintained on prophylactic treatment for 6 to 12 months
after the initial episode. Aggravating factors such as alcohol
or cocaine use and cigarette smoking should be stopped.
• Nitrates are the mainstay of therapy, and most patients
respond rapidly to SL nitroglycerin or ISDN. IV and
intracoronary nitroglycerin may be useful for patients not
responding to SL preparations. Because CCB may be more
effective, have few serious adverse effects, and can be
given less frequently than nitrates, some authorities
consider them the agents of choice for variant angina.
Nifedipine, verapamil, and diltiazem are all equally
effective as single agents for initial management. Patients
unresponsive to CCB alone may have nitrates added.
Combination therapy with nifedipine plus diltiazem or
nifedipine plus verapamil is reported to be useful in patients
unresponsive to single-drug regimens.
• β-Blockers have little or no role in the management of
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variant
angina
as
they
may
induce
coronary
vasoconstriction and prolong ischemia.
EVALUATION OF THERAPEUTIC OUTCOMES
• Subjective measures of drug response include the
number of painful episodes, amount of rapid-acting
nitroglycerin consumed, and patient reported alterations
in activities of daily living (e.g., time to walk two blocks,
number of stairs climbed without pain).
• Objective clinical measures of response include HR,
blood pressure.
• Objective assessment also includes the resolution of
ECG changes at rest, during exercise, or with
ambulatory ECG monitoring.
• Monitoring for major adverse effects should be
undertaken; they include headache and dizziness with
nitrates; fatigue and lassitude with β-blockers; and
peripheral edema, constipation, and dizziness with
calcium channel antagonists.
• A comprehensive plan includes ancillary monitoring of
lipid profiles, fasting plasma glucose, thyroid function
tests, hemoglobin/hematocrit, and electrolytes.
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